TY - JOUR
T1 - A critical role for PKR complexes with TRBP in immunometabolic regulation and eIF2α phosphorylation in obesity
AU - Nakamura, Takahisa
AU - Kunz, Ryan C.
AU - Zhang, Cai
AU - Kimura, Taishi
AU - Yuan, Celvie L.
AU - Baccaro, Brenna
AU - Namiki, Yuka
AU - Gygi, Steven P.
AU - Hotamisligil, Gökhan S.
N1 - Funding Information:
We thank all members of the Hotamisligil lab for their scientific input and contribution, especially Kathryn Claiborn, Ariane Panzer, Ling Yang, Gurol Tuncman, Suneng Fu, and Alessandro Arduini for support and discussion. We thank Ed Huttlin, Deepak Kolippakkam, and Kazuishi Kubota from the Gygi lab for their statistical and bioinformatics discussion. Dicer- and TRBP-deficient fibroblasts were kindly provided by Zissimos Mourelatos and Anne Gatignol, respectively. We also thank James R. Mitchell for helpful discussion. This study was supported in part by grants from the National Institutes of Health (DK052539 and HL125753 to G.S.H.). Parts of this study were supported by a fellowship from the International Human Frontier Science Program and a grant from NIDDK P30 DK078392 (Gene and Protein Expression Core) of the Digestive Disease Research Core Center in Cincinnati (to T.N.). T.N. is supported by a Scientist Development Grant from the American Heart Association and PRESTO from the Japan Science and Technology Agency.
PY - 2015
Y1 - 2015
N2 - Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading toPKRactivation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2α phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease.
AB - Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading toPKRactivation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2α phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease.
UR - http://www.scopus.com/inward/record.url?scp=84928127446&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928127446&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.03.021
DO - 10.1016/j.celrep.2015.03.021
M3 - Article
C2 - 25843719
AN - SCOPUS:84928127446
VL - 11
SP - 295
EP - 307
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 2
ER -
